PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome (CPKC412A2104 Core); and PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome With Either Wild Type or Mutated FMS-like Tyrosine Kinase 3 (FLT3) (CPKC412A2104E1 and CPKC412A2104E2)

NCT00045942 | Completed Phase 1 Results FDA Drug

• 1 other identifier: CPKC412A2104
• Study Type: interventional
• Target: 144
• Locations: 1 country
• Sites: 4

Brief Summary

CPKC412A2104 core had a 2 stage design. In stage 1, eight participants were treated. If at least one participant showed a clinical response, four more participants were recruited to stage 2. The trial was to be stopped if no participants showed a response in stage 1. POC was achieved if at least 2 participants out of 12 responded. In PKC412A2104E1, participants with AML or high risk MDS with wild-type or mutant FTL3 who had not previously received a FLT3 inhibitor were randomized to receive continuous twice daily oral doses of either 50 or 100 mg midostaurin in 1 28-day cycle regimen. Participants were to be treated until disease progression or the occurrence of unacceptable treatment-related toxicity. PKC412A2104 E2 contained 2 dosing regimens: 1) intra-participant midostaurin dose escalation and 2) midostaurin with itraconazole in participants with AML and high risk MDS irrespective of FLT3 status. Eligible participants were alternately assigned to the regimens. At the Investigator's discretion, intra-participant dose escalation was allowed for any previously enrolled CPKC412A2104E1 participant receiving midostaurin at the time of the approval of amendment 4. Participants were treated until the time of disease progression.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

AML; MDS; high risk myelodysplastic syndrome

Outcome Measures

Primary Outcomes (22)

• Number of Participants With Best Clinical Response (Core)

  Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.

  from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003

• Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)

  days 1, 28

• Number of Participants With Overall Clinical Response (E1)

  Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.

  from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

• Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)

  days 1, 28

• Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)

  Days 1, 28

• Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for PKC412 Plasma in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21 and 22

• Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP62221 Plasma in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP622221 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: day 22,

• Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP52421 Plasma in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)

  Blood samples were collected for pharmacokinetic (PK) analysis.

  Cycle 1: days 21, 22, 28

• Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)

  Blood samples were collected for PK analysis.

  Cycle 1: days 21, 22, 28

• Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)

  Blood samples were collected for analysis.

  Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

• Summary of CGP62221 Concentration (E2)

  Blood samples were collected for analysis.

  Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

• Summary of CGP52421 Concentration (E2)

  Blood samples were collected for analysis.

  Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15

Secondary Outcomes (17)

• Time to Disease Progression (TTP) (Core)

  from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003

• Summary of Midostaurin Plasma Concentration (Core)

  Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

• Summary of CGP62221 Plasma Concentration (Core)

  Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

• Summary of CGP52421 Plasma Concentration (Core)

  Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

• Time to Disease Progression (E1)

  from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Study Arms (9)

PKC412 (Core)

EXPERIMENTAL

Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Drug: PKC412

FLT3 mutated PKC412 100 mg/day (E1)

EXPERIMENTAL

Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Drug: PKC412

FLT3 mutated PKC412 200 mg/day (E1)

EXPERIMENTAL

Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Drug: PKC412

FLT3 wild type PKC412 100 mg/day (E1)

EXPERIMENTAL

Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Drug: PKC412

FLT3 wild type PKC412 200 mg/day (E1)

EXPERIMENTAL

Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.

Drug: PKC412

FLT3 mutated PKC412 dose escalation

EXPERIMENTAL

Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.

Drug: PKC412

FLT3 mutated PKC+Itraconazole (E2)

EXPERIMENTAL

Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Drug: Itraconazole; Drug: PKC412

FLT3 wild type PKC412 dose escalation (E2)

EXPERIMENTAL

Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.

Drug: PKC412

FLT3 wild type PKC+Itraconazole (E2)

EXPERIMENTAL

Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Drug: Itraconazole; Drug: PKC412

Interventions

Itraconazole DRUG

Itraconazole was commercially available.

FLT3 mutated PKC+Itraconazole (E2); FLT3 wild type PKC+Itraconazole (E2)

PKC412 DRUG

PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.

Also known as: Midostaurin

FLT3 mutated PKC+Itraconazole (E2); FLT3 mutated PKC412 100 mg/day (E1); FLT3 mutated PKC412 200 mg/day (E1); FLT3 mutated PKC412 dose escalation; FLT3 wild type PKC+Itraconazole (E2); FLT3 wild type PKC412 100 mg/day (E1); FLT3 wild type PKC412 200 mg/day (E1); FLT3 wild type PKC412 dose escalation (E2); PKC412 (Core)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients:
• with AML who are not candidates for myelosuppressive chemotherapy or with AML who have relapsed disease or are refractory to standard therapy and not likely to require cytoreductive therapy within one month or with MDS subtypes refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T) or chronic myelomonocytic leukemia (CMML).
• Patients with a relevant FLT3-ITD mutation or D835Y point mutation
• Patients at least 18 years or older
• Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months
• Patients must not be treated within 4 weeks after any prior therapy
• Written informed consent obtained according to local guidelines

You may not qualify if:

• Patients meeting any of the following criteria during screening will be excluded from entry into the study:
• Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously.
• Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control.
• Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (4)

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

New York Weill Cornell Medical Center

New York, New York, 10021, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Itraconazole; midostaurin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Results Point of Contact

• Title: Study Director
• Organization: Novartis

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2002
• First Posted: September 18, 2002
• Study Start: January 30, 2002
• Primary Completion: March 27, 2008
• Study Completion: March 27, 2008
• Last Updated: August 11, 2017
• Results First Posted: July 17, 2017

Record last verified: 2017-08

Locations

US (4)